Curcumin, a yellow polyphenol compound found in the Indian spice turmeric (Curcuma longa) demonstrates potent anti-cancer effects against a wide variety of human tumor models in preclinical studies. A major pitfall for the application of curcumin to human cancer therapy has been its limited systemic bioavailability, such that the few clinical trials conducted so far had administered mega doses (8-10 grams) of free curcumin daily to patients in order to yield detectable levels. These high dosages significantly affect patient compliance and have stymied the application of this promising, and relatively non-toxic, agent to most visceral malignancies that would mandate high plasma levels of the active therapeutic. A novel nanoparticle encapsulated formulation of curcumin (nanocurcumin) has been engineered which bypasses the bioavailability pitfall of this compound, and enables strikingly higher circulating and tissue levels upon parenteral administration. Nanocurcumin causes significant growth reduction of subcutaneous and orthotopic pancreatic cancer xenografts, and abrogates systemic metastases when co-administered with gemcitabine in a spontaneously metastatic animal model. The studies proposed herein have the overarching goal of performing the efficacy, pharmacokinetics, and toxicity data required for filing an investigational new drug (IND) application with the USFDA. To this effect, nanocurcumin (as single agent or in combination with gemcitabine) will be tested in a panel of low-passage gemcitabine-resistant patientderived orthotopic xenografts (Aim 1) and in a uniformly lethal genetically engineered mouse model (Aim 2), and will undergo regulatory grade in vitro and in vivo toxicology testing by the federally-funded Nanotechnology Characterization Laboratory (NCL) (Aim 3), in preparation for a pre-IND application. Two hypothesis-driven aims that integrate unique CCNE resources will also be pursued, including the effects of nanocurcumin on vaccine efficacy and quantifiable measures of cellular immune response (Aim 4; in collaboration with Project 3) and engineering the next generation of active-targeted antibody-conjugated nanocurcumin (Aim 6; in collaboration with the Nanoparticle Engineering and the Validation Cores).